Numb downregulation suppresses cell growth and is associated with a poor prognosis of human hepatocellular carcinoma

Abstract

Numb, an endocytic adaptor, is a known cell fate determinant that participates in asymmetric cell division. The present study aimed to explore the potential roles of Numb in hepatocarcinogenesis. Numb expression was investigated in hepatocellular carcinomas (HCC) with reverse transcription-quantitative polymerase chain reaction and immunohistochemical examination; its association with the prognosis of HCC patients was analyzed. In addition, the effects of Numb deletion on proliferation of HCC cells and its relevant molecules were evaluated in Huh7 and HepG2 cells. Numb overexpression was observed in 62% of adjacent non-tumor tissues and 46% of tumor tissues. Overexpression of Numb in HCC was associated with histological grade, portal vein invasion and the number of tumors (P=0.001, 0.022 and 0.034 respectively). Multivariate analysis revealed that Numb expression was an independent prognostic indicator of HCC patients. Methylation of the Numb promoter contributed to hepatocarcinogenesis. In vitro assays demonstrated that Numb silencing resulted in inhibition of cell proliferation, induction of apoptosis, down-regulation of cyclin-dependent protein kinase 4 (CDK4) and S-phase kinase-associated protein 2 (SKP2), and upregulation of Bcl-2 homologous antagonist/killer (BAK) and cyclin-dependent kinase inhibitor 1 (p21). The present study suggests that downregulation of Numb inhibits colony formation and cell proliferation, induces apoptosis of HCC cells and independently predicts the poor prognosis of HCC patients. Thus, Numb has a potential role in the development and progression of HCC.

Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma

“…Although the present study observed interactions between Numb and the Notch pathway in lung ADC, the contribution of the other pathways to the tumor suppressive role of Numb requires further investigation. Whereas, it has been reported that Numb promotes cell proliferation and cell cycle of hepatocellular carcinoma, inhibiting p21 and modulating CDK4 and SKP2 [ 13 , 35 ]. Numb might interact with cell cycle molecules to promote the growth of lung SCC, although we have not yet investigated this.…”

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.)

“…The 5-year survival rate of HCC patients is 50–70% ( Xie et al, 2015 ). Currently, liver transplantation is the only effective curative modality.…”

Numb−/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling

“…Recently, a growing body of evidence has suggested that Numb may act as a tumor suppressor in various tumor types, including hepatocellular carcinoma, malignant pleural mesothelioma, and breast cancer (16)(17)(18). The downregulation of Numb is associated with a poor prognosis in hepatocellular carcinoma (19), salivary gland carcinoma (20), and esophageal squamous cell carcinoma (21). However, the expression of Numb is greatly heterogeneous among different cells within a tumor mass (22)(23)(24).…”